Vitamin D deficiency and depression in adults: systematic review and meta-analysis
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The British Journal of Psychiatry (2013)
202, 100–107. doi: 10.1192/bjp.bp.111.106666
Review article
Vitamin D deficiency and depression in adults:
systematic review and meta-analysis
Rebecca E. S. Anglin, Zainab Samaan, Stephen D. Walter and Sarah D. McDonald
Background
There is conflicting evidence about the relationship between 95% CI 0.23–0.97) and there was an increased odds ratio of
vitamin D deficiency and depression, and a systematic depression for the lowest v. highest vitamin D categories in
assessment of the literature has not been available. the cross-sectional studies (OR = 1.31, 95% CI 1.0–1.71). The
cohort studies showed a significantly increased hazard ratio
Aims of depression for the lowest v. highest vitamin D categories
To determine the relationship, if any, between vitamin D (HR = 2.21, 95% CI 1.40–3.49).
deficiency and depression.
Method Conclusions
A systematic review and meta-analysis of observational Our analyses are consistent with the hypothesis that low
studies and randomised controlled trials was conducted. vitamin D concentration is associated with depression, and
highlight the need for randomised controlled trials of vitamin
Results D for the prevention and treatment of depression to
One case–control study, ten cross-sectional studies and determine whether this association is causal.
three cohort studies with a total of 31 424 participants
were analysed. Lower vitamin D levels were found in Declaration of interest
people with depression compared with controls (SMD = 0.60, None.
Depression is associated with significant disability, mortality and
Method
healthcare costs. It is the third leading cause of disability in
high-income countries,1 and affects approximately 840 million Search strategy
people worldwide.2 Although biological, psychological and
We searched the databases MEDLINE, EMBASE, PsycINFO,
environmental theories have been advanced,3 the underlying
CINAHL, AMED and Cochrane CENTRAL (up to 2 February
pathophysiology of depression remains unknown and it is
2011) using separate comprehensive strategies developed in
probable that several different mechanisms are involved. Vitamin
consultation with an experienced research librarian (see online
D is a unique neurosteroid hormone that may have an important
supplement DS1). A separate search of PubMed identified articles
role in the development of depression. Receptors for vitamin D
published electronically prior to print publication within 6
are present on neurons and glia in many areas of the brain
months of our search and therefore not available through
including the cingulate cortex and hippocampus, which have been
MEDLINE. The clinical trials registries clinicaltrials.gov and
implicated in the pathophysiology of depression.4 Vitamin D is
Current Controlled Trials (controlled-trials.com) were searched
involved in numerous brain processes including neuroimmuno-
for unpublished data. The reference lists of identified articles were
modulation, regulation of neurotrophic factors, neuroprotection,
reviewed for additional studies.
neuroplasticity and brain development,5 making it biologically
plausible that this vitamin might be associated with depression
and that its supplementation might play an important part in Eligibility criteria
the treatment of depression. Over two-thirds of the populations The following study designs were included: RCTs, case–control
of the USA and Canada have suboptimal levels of vitamin D.6,7 studies, cross-sectional studies and cohort studies. All studies
Some studies have demonstrated a strong relationship between enrolled adults (age 18 years) and reported depression as the
vitamin D and depression,8,9 whereas others have shown no outcome of interest and vitamin D measurements as a risk factor
relationship.10,11 To date there have been eight narrative reviews or intervention. Cross-sectional and cohort studies were required
on this topic,12–19 with the majority of reviews reporting that there to report depression outcomes for participants with vitamin D
is insufficient evidence for an association between vitamin D and deficiency (as defined by each study, see Tables 1 and 2) compared
depression. None of these reviews used a comprehensive search with those with normal vitamin D levels. There was no language
strategy, provided inclusion or exclusion criteria, assessed risk of restriction. Eligibility criteria are detailed in online supplement
bias or combined study findings. In addition, several recent DS2.
studies were not included in these reviews.9,10,20,21 Therefore, we
undertook a systematic review and meta-analysis to investigate
whether vitamin D deficiency is associated with depression in Outcome
adults in case–control and cross-sectional studies; whether Our primary outcome for all studies was depression diagnosed
vitamin D deficiency increases the risk of developing depression in using one of the following:
cohort studies in adults; and whether vitamin D supplementation
improves depressive symptoms in adults with depression compared (a) a standardised psychiatric interview for the DSM diagnoses of
with placebo, or prevents depression compared with placebo, in depressive disorders (e.g. the Structured Clinical Interview for
healthy adults in randomised controlled trials (RCTs). DSM Disorders) or ICD diagnoses of a depressive episode or
100Vitamin D and depression
depression (e.g. the Composite International Diagnostic intervals. We planned to pool the adjusted ORs for meta-analysis.
Interview);22,23 Unfortunately the cross-sectional studies used different reference
(b) a clinical diagnosis of a depressive disorder, depressive episode categories of vitamin D concentration (either 550 nmol/l or the
or depression not otherwise specified; lowest and highest category) and presented data using different
quartiles, tertiles or categories. After protocol development, but
(c) a diagnosis of depression using an established cut-off point on prior to analysing the data, we decided to use the adjusted OR
a validated rating scale, such as a score of 516 on the Center of depression for the lowest v. highest vitamin D categories
for Epidemiological Studies – Depression scale or 58 on the reported. The inverse variance method and random effects model
Geriatric Depression Scale.24,25 were used for all meta-analyses. A random effects model was
For RCTs that enrolled patients with depression our secondary chosen because we anticipated heterogeneity among studies.
outcome was change in depressive symptoms using a validated Where ORs were reported for subgroups of patients within a
rating scale. This secondary outcome was not used for RCTs single study, they were combined into a single OR for our
that enrolled non-depressed participants or other study designs analysis.30
because it was not meaningful in those contexts.
Cohort studies
Study selection and data abstraction As with the analysis of cross-sectional studies, the variability in
Two authors (R.A. and Z.S.) independently reviewed all titles presentation of results of the cohort studies precluded the
and abstracts identified by the search. Articles were selected for calculation of a pooled adjusted OR. We therefore contacted the
full-text review if inclusion criteria were met or if either reviewer authors of all three cohort studies to obtain the number of
considered them potentially relevant. Disagreements were resolved depressed participants and the person-years of follow-up in each
by discussion between the two reviewers, and a third author category of vitamin D, and requested data using the cut-off point
(S.M.) was available to determine eligibility if consensus could of 50 nmol/l. This allowed us to calculate hazard rates for each
not be reached. Initial agreement was assessed using an category, so that we could then account for losses to follow-up
unweighted k value. Data were extracted by two authors (R.A. and variable follow-up periods; also, by assuming a constant
and Z.S.) independently using a form developed for this review, hazard rate over time, we could pool hazard ratios using a cut-
with disagreements resolved as above. We attempted to contact off point of 50 nmol/l. All authors provided some data, but one
study authors for additional or missing information when needed. provided only data using the cut-off points of 37.5 nmol/l and
75 nmol/l.9 We therefore performed a sensitivity analysis using
Assessment of risk of bias these two cut-off points in a meta-analysis.
Additionally, we decided to analyse the cohort data using the
Two reviewers (R.A. and Z.S.) independently assessed the risk
highest v. lowest vitamin D categories in order to use the adjusted
of bias using a modified Newcastle–Ottawa Scale (see online
results and take confounding into account. For this analysis the
supplement DS3).26 In observational studies one of the main
adjusted hazard ratios were used; the adjusted OR from one study
sources of bias is confounding. Known confounders can be
was converted first to a relative risk and then to a hazard ratio
statistically adjusted, but unknown confounders may still result
(HR).10 Finally, we performed a third analysis in which we
in bias. It was decided a priori that studies that adjusted for factors
calculated the increase in the natural logarithm of the hazard rate
shown elsewhere to affect vitamin D levels (chronic disease, body
(ln(HR)) of depression per 20 nmol/l decrease in vitamin D for
mass index, geographical location, season and physical
each study.31 The mid-point of each category of vitamin D was
activity)27,28 would be considered to have a low risk of bias,
calculated and half the width of the adjacent category was used
studies that adjusted only for other potential confounders would
to define the corresponding point for open-ended categories.
have an unclear risk of bias, and any studies that did not adjust
The ln(HR) for each category was then regressed on the vitamin
for any confounders would have a high risk of bias. Publication
D mid-points (divided by 20) using a linear model, with the data
bias was assessed using funnel plots.
weighted by the inverse variance of the ln(HR), to generate a
coefficient that represented the change in ln(HR) per 20 nmol/l
Statistical analysis decrease in vitamin D and its associated standard error. The
Search results were compiled using citation management software coefficients for each study were then pooled for meta-analysis.
(RefWorks version 2.0; ProQuest, http://www.refworks.com).
Statistical analysis was performed using Review Manager software Assessment of heterogeneity
(Revman version 5.1; Cochrane Collaboration, Oxford, UK),
Heterogeneity between the studies was measured using Cochran’s
Epi Info version 6.0 (CDC, Atlanta, Georgia, USA) and PASW
Q statistic, with a probability value of P50.05 (two-tailed)
Statistics version 18.0 (SPSS, Chicago, Illinois, USA) for Mac.
considered statistically significant. The I 2 statistic was used to
quantify the degree of heterogeneity and we considered values
Case–control studies below 25% to be low, 25–50% moderate and over 50% high.32
The standardised mean difference (SMD) of vitamin D levels
between the participants with depression and the healthy controls Subgroup and sensitivity analyses
was calculated. An SMD below 0.4 was considered small, 0.4–0.7
moderate and over 0.7 large.29 Our protocol proposed pooling We planned the following subgroup analyses a priori: gender, age
SMDs for meta-analysis using a random effects model. 565 years, prevalence of vitamin D deficiency, proportion of
participants with a disease known to affect vitamin D, and
adjustment for different confounders. We planned a priori to
Cross-sectional studies perform a sensitivity analysis excluding studies with a high risk
Our protocol proposed examining adjusted odds ratios (ORs) of of bias. For the cohort studies we performed a sensitivity analysis
depression for those with or without vitamin D deficiency (as using the cut-off point of 37.5 nmol/l compared with 75 nmol/l for
defined in each study) and the associated 95% confidence the one study that did not provide data using our standard cut-off
101Anglin et al
point of 50 nmol/l. We also performed a sensitivity analysis for the Risk of bias in included studies
cross-sectional studies excluding one study that had recruited Case–control study
participants aged 15–39 years33 (our inclusion criteria specified
adults aged 18 years). The agreement between the reviewers in assessing the risk of
bias for the case–control study across the nine points of the
Newcastle–Ottawa Scale was 100%, with both reviewers assigning
Results the same four points. There was potential for selection bias as
participants were recruited through advertisements and were all
Our primary search identified 6675 citations (Fig. 1). No premenopausal women; also, the study did not control for known
additional article or abstract was selected from other sources. After confounders.
duplicates were removed 5484 citations remained for title and
abstract screening. Of these, 35 were identified and retrieved for Cross-sectional studies
full-text screening; all were in English. After full text review, one
Agreement between the reviewers in assessing the risk of bias in
case–control study,34 three cohort studies,9,10,35 and ten cross-
cross-sectional studies was 95%, unweighted k = 0.84. Four studies
sectional studies,8,11,20,21,30,33,36–39 met eligibility criteria and were
included (unweighted k = 0.75). Figure 1 lists the reasons for were thought to be unrepresentative of the general population:
excluding the other studies.19,40–58 Johnson et al included only low-income older adults;20 Lee et al
included only elderly men;37 and the two studies by Wilkins et
al included only elderly participants, half of whom in the 2006
Study characteristics study were purposely selected to have Alzheimer’s disease, and
in the 2009 study were purposely selected to include African
Baseline information on the case–control, cross-sectional and
Americans and European Americans in equal numbers.8,39 Seven
cohort studies is presented in Tables 1 and 2. There were 31 424
studies received a high risk of bias assignment for assessment of
participants in total. All studies were published between 2006
outcome because they used cut-off points on self-reported
and 2011; study locations included the USA, Europe and East
psychiatric rating scales. Two studies received an unclear risk of
Asia. Seven of the ten cross-sectional studies included older adults.
bias assignment for using administered surveys, which were felt
to have an intermediate risk of bias between a self-report scale
and clinician-administered standardised psychiatric interview.
Citations from MEDLINE, All studies adjusted for multiple confounders (online supplement
EMBASE, CINAHL, Additional records
AMED, CENTRAL, PsychINFO identified through DS4). The funnel plot (online supplement DS5) did not suggest
other sources
and PubMed searches
0
significant publication bias.
6675
Cohort studies
Agreement between the reviewers in assessing the risk of bias
Records after across cohort studies was 88%, unweighted k = 0.61. Two studies9,10
duplicates removed were considered unrepresentative of the general population, and
5485
the study by May et al was thought to be at high risk of bias for
selection of the non-exposed cohort because vitamin D levels were
obtained at the discretion of treating physicians,9 which may have
Records screened biased whose vitamin D levels were observed. All studies included
Full-text articles excluded 20:
5485 in this review adjusted for multiple confounders, but May et al did
3 cross-sectional studies did
not report depression outcomes not measure or adjust for physical activity, body mass index or the
for those with vitamin D presence of chronic diseases and therefore received an unclear risk
deficiency v. normal
vitamin D19,40,41 in 14 studies of bias rating. Chan et al and Milaneschi et al used cut-off points
Full-text articles
assessed for
depression as defined by on self-report scales to diagnose depression,10,35 which is less
our protocol was not
eligibility
reported42–55
reliable than a clinical diagnosis, and therefore these studies were
35 rated at high risk of bias. Although May et al used a clinical
1 trial of open treatment with
vitamin D did not report diagnosis of depression using ICD-9 codes, it was not clear
depression as an outcome56
1 summary report of another whether all participants underwent a clinical assessment or
study57 whether record linkage was used; an unclear risk of bias was
Studies included in
1 thesis with insufficient therefore assigned. May et al presented the average duration of
qualitative synthesis
information (author did not
15 follow-up period but did not otherwise describe loss to follow-up,
respond to request for more
(1 case-control,
information)58 and therefore this received an unclear rating. Because there were
3 cohort,
10 cross-sectional) only three cohort studies the funnel plot was uninformative.59
Further information on the risk of bias assessments is included
in online supplement DS5.
Studies included in
quantitative synthesis Outcome evaluation and meta-analysis
(meta-analysis)
13 A summary of the results from the cross-sectional and cohort
(3 cohort and meta-analyses including subgroup and sensitivity analyses is
9 cross-sectional)
presented in Table 3. Three cross-sectional studies did not
report ORs, and the authors of these studies were contacted.20,36,39
Fig. 1 Study selection process.
One author replied and the OR provided was included in the
meta-analysis;36 an unadjusted OR and 95% CI were calculated
102Vitamin D and depression
Table 1 Characteristics of included studies: case–control and cross-sectional studies
Mean Categories
age, Diagnosis of vitamin D, Measurement
Study, year Country Population years n of depression nmol/l of vitamin D
Case–control studies
Eskandari (2007)34 USA Women aged 21–45 years 35 133 SCID NA CPBA
Cross-sectional studies
Ganji (2010)33 USA Men and women 27.5 7970 DIS 550, 50–75, 475 RIA
aged 15–39 years
Hoogendijk (2008)36 The Men and women 75.1 1282 Score 516 on CES-D Cut-off point 50 CPBA
Netherlands aged 65–95 years
Johnson (2008)20 USA Older adults 77 158 Score 511 on GDS-10 525, 25–50, >50 RIA
Lee (2011)37 Several Men aged 40–79 years 59.7 3151 Score 514 BDI-II 525, 25–49.9, 50–74.9, 475 RIA
European
countries
Nanri (2009)30 Japan Men and women 43.4 527 Score 516 on CES-D Quartiles (medians 53.75, CPBA
aged 21–67 years 64.75, 72.5, 82)
11
Pan (2009) China Men and women NR 3262 Score 516 on CES-D Quartiles (means 26.1, 41.1, RIA
aged 50–70 years 65.1)
Stewart (2010)38 UK Men and women 73.7 2070 Score 53 on GDS-10 525, 550, 575 RIA
aged 565 years
Wilkins (2006)8 USA Men and women 74.5 80 Depression Symptoms 525, 25–50, 450 RIA
aged 460 years Inventory
Wilkins (2009)39 USA Men and women 74.99 60 Depressive Features Cut-off point 50 CPBA
aged 455 years Inventory
Zhao (2010)21 USA Men and women NR 3916 Score 510 on PHQ-9 537.5, 37.5–50, 50–65, 465 RIA
aged 520 years
Total cross-sectional studies 22 476
BDI, Beck Depression Inventory; CES-D, Center for Epidemiological Studies – Depression scale; CPBA, competitive protein binding assay; DIS, Diagnostic Interview Schedule; GDS,
Geriatric Depression Scale; NA, not applicable; NR, not reported; PHQ, Patient Health Questionnaire; RIA, radioimmunoassay; SCID, Structured Clinical Interview for DSM-IV.
Table 2 Characteristics of included studies: cohort studies
Categories of Loss to Length of
Mean age, Diagnosis vitamin D, Measurement follow-up, follow-up,
Study, year Country Population years n of depression nmol/l of vitamin D % years
Chan (2011)10 China Men aged 72.5 801 Score 8 Quartiles (563, 64–76, 77– RIA 21 4
465 years on GDS 91, 492) and categories
(550, 50–74, 75–99, 4100)
May (2010)9 USA Cardiovascular 73.1 7358 Clinical Categories (537.5, 37.5–75, CIA NRa 1b
patients aged diagnosis 75–125, 4125
550 years
Milaneschi Italy Men and women 74.4 656 Score 516 on Tertiles (531.7, 31.7–53.9, RIA 3 6
(2010)39 aged 565 years CES-D 453.9) and cut-off point
(550 or 550)
Total cohort studies 8815
CIA, chemiluminescent immunoassay; CES-D, Center for Epidemiological Studies – Depression scale; GDS, Geriatric Depression Scale; NR, not reported; RIA, radioimmunoassay.
a. Most of cohort (71%) ‘not evaluable’ at 500 days.
b. Mean follow-up period.
for another study using data provided in the paper and Epi Info highest vitamin D categories, with a pooled OR of 1.31, 95% CI
version 6.0,39 but the third study could not be included.20 1.00–1.71 (Fig. 2). There was substantial heterogeneity between
studies (I 2 = 54%, w2 = 17.24, P = 0.03). The only subgroup
Case–control study analysis that could be performed was of studies that had an
One study compared vitamin D levels in women with depression average sample age of 65 years (online supplement DS5). When
and healthy controls.34 The mean difference between the groups these studies were combined there was an increased – although
was 17.5 nmol/l (P = 0.002), with an SMD of 0.60 (95% CI non-significant – odds of depression with low vitamin D
0.23–0.97). This represented a moderate difference,29 which was (OR = 1.54, 95% CI 1.00–2.40). A sensitivity analysis excluding
also clinically significant. Meta-analysis could not be performed the study by Ganji et al (online supplement DS6) had a minimal
as only one study met our inclusion criteria. effect on our summary estimate (OR = 1.34, 95% CI 0.99–1.83,
I 2 = 59%, w2 = 17.16, P = 0.02).33
Cross-sectional studies
The cross-sectional studies measured rates of depression and Cohort studies
vitamin D in a population at a single point in time to determine Three studies measured vitamin D levels at baseline in non-
whether there was an association between depression and vitamin depressed individuals and followed them over time to determine
D levels. Nine studies reported on depression for the lowest v. the whether vitamin D levels were associated with a risk of developing
103Anglin et al
Table 3 Summary of results from the meta-analysis of cross-sectional and cohort studies of the relationship between vitamin D
and depression
Number Participants
of studies n Vitamin D categories Pooled OR or HR (95% CI) I 2, %
Cross-sectional studies
All studies 9 22 318 Lowest v. highest OR = 1.31 (1.00 to 1.71) 5 (P = 0.03)
Older adults 4 3492 Lowest v. highest OR = 1.54 (1.00 to 2.40) 49 (P = 0.12)
Cohort studies
3 8815 Lowest v. highest HR = 2.21 (1.40 to 3.49) 21 (P = 0.28)
3 8815 Change in HR depression per 20 nmol/l b70.19 (70.41 to 004) 100 (P50.00001)
change in vitamin D
3 8815 Vitamin D cut-off points of 50 nmol/l HR = 1.04 (0.59 to 1.86) 98 (P50.00001)
and 37.5 nmol/l (May et al)
3 8815 Vitamin D cut-off points of 50 nmol/l HR = 1.31 (0.97 to 1.77) 91 (P50.0001)
and 75 nmol/l (May et al)
HR, hazard rate; OR, odds ratio.
Odds Ratio Odds Ratio
Study or subgroup log (OR) s.e. Weight, % IV, random, 95% CI IV, random, 95% CI
Ganji (2010)33 0.16 0.25 13.1 1.17 (0.72, 1.92)
38
Hoogendijk (2008)2008) 0.29 0.19 16.1 1.34 (0.92, 1.94)
Lee (2011)37 0.55 0.27 12.2 1.73 (1.02, 2.94)
Nanri (2009)30 0.48 0.29 11.3 1.62 (0.92, 2.85)
Pan (2009)11 70.3 0.19 16.1 0.74 (0.51, 1.08)
Stewart (2010)38 0.38 0.18 16.6 1.46 (1.03, 2.08)
Wilkins (2006)8 2.46 0.89 2.1 11.70 (2.05, 66.98) 7
Wilkins (2009)39 0.086 0.68 3.4 1.09 (0.29, 4.13)
Zhao (2010)21 0.11 0.35 9.2 1.12 (0.56, 2.22)
Total (95% CI) 100.0 1.31 (1.00, 1.71)
Heterogeneity: t2 = 0.08; w2 = 17.24, d.f. = 8 (P = 0.03); I 2 = 54%
Test for overall effect: Z = 1.98 (P = 0.05) 0.2 0.5 1 2 5
Fig. 2 Cross-sectional studies: forest plot of the odds ratio (OR) of depression for the lowest v. highest vitamin D categories. Squares
to the right of the vertical line indicate that low vitamin D was associated with increased odds of depression, squares to the left of the
vertical line indicate that low vitamin D was associated with decreased odds of depression. Horizontal lines represent the associated
95% confidence intervals and the diamond represents the overall OR of depression with low vitamin D from the meta-analysis and the
corresponding 95% confidence interval (*OR provided by Dr B. Penninx, personal communication, 25 July 2011).
Hazard Ratio Hazard Ratio
Study or subgroup log (HR) s.e. Weight, % IV, random 95% CI IV, random, 95% CI
Chan (2011)10 70.48 0.86 7.0 0.62 (0.11, 3.34)
May (2010)9 0.99 0.35 33.7 2.69 (1.36, 5.34)
Milaneschi (2010)35 0.83 0.23 59.3 2.29 (1.46, 3.60)
Total (95% CI) 100.0 2.21 (1.40, 3.49)
Heterogeneity: t2 = 0.04; w2 = 2.52, d.f. = 2 (P = 0.28); I 2 = 21%
Test for overall effect: Z = 3.40 (P = 0.0007) 0.01 0.1 1 10 100
Fig. 3 Cohort studies: forest plot of the hazard ratio (HR) of depression for the lowest v. highest vitamin D categories. Squares to the
right of the vertical line indicate that vitamin D deficiency was associated with an increased risk of depression, whereas squares to the left
of the vertical line indicate that vitamin D deficiency was associated with a decreased risk of depression. Horizontal lines represent the
associated 95% confidence intervals and the diamond represents the overall HR of depression with vitamin D deficiency from the meta-
analysis and the corresponding 95% confidence interval.
depression. There was a statistically significant increased risk of vitamin D level was calculated for each study and pooled. There
depression with low vitamin D (HR = 2.21, 95% CI 1.40–3.49) was a non-significant decreased ln(HR) of depression for each
with non-significant heterogeneity (I 2 = 21%, w2 = 2.52, P = 0.28) 20 nmol/l increase in vitamin D (b = 70.19, 95% CI 70.41 to
when the HRs for depression for the lowest v. highest vitamin 0.04; Fig. 4).
D categories in the three cohort studies were pooled (Fig. 3). The HRs of depression for those with and without vitamin D
The change in the ln(HR) of depression per 20 nmol/l change in levels below 50 nmol/l from the studies by Chan et al and
104Vitamin D and depression
Beta Beta
Study or subgroup Beta s.e. Weight, % IV, random, 95% CI IV, random, 95% CI
Chan (2011)10 70.184 0.15 23.1 70.18 (70.48, 0.11)
May (2010)9 70.059 0.008 38.4 70.06 (70.07, 70.04)
Milaneschi (2010)35 70.319 0.005 38.5 70.32 (70.33, 70.31)
Total (95% CI) 100.00 70.19 (70.41, 0.04)
Heterogeneity: t2 = 0.03; w2 = 7.59, d.f. = 2 (P50.00001); I 2 = 100%
Test for overall effect: Z = 1.65 (P = 0.10) 71 70.5 0 0.5 1
Fig. 4 Cohort studies: forest plot of the change in the natural logarithm of the hazard rate ln(HR) of depression per 20 nmol/l change
in vitamin D using trend estimation. Squares to the right of the vertical line indicate a positive slope or increased risk of depression
with increased vitamin D levels, whereas squares to the left indicate a negative slope or decreased risk of depression with increased
vitamin D levels. Horizontal lines represent the associated 95% confidence intervals and the diamond represents the overall change in
ln(HR) of depression per 20 nmol/l change in vitamin D from the meta-analysis and the corresponding 95% confidence interval.
Hazard Ratio Hazard Ratio
Study or subgroup log (HR) s.e. Weight, % IV, random, 95% CI IV, random, 95% CI
Chan (2011)10 70.3014 0.17883 31.0 0.74 (0.52, 1.05)
May (2010)9 70.1851 0.03034 34.9 0.83 (0.78, 0.88)
Milaneschi (2010)35 0.5905 0.08063 34.1 1.80 (1.54, 2.11)
Total (95% CI) 100.0 1.04 (0.59, 1.86)
Heterogeneity: t2 = 0.25; w2 = 82.43, d.f. = 2 (P50.00001); I 2 = 98%
Test for overall effect: Z = 0.15 (P = 0.88) 0.2 0.5 1 2 5
Fig. 5 Cohort studies: forest plot of the hazard ratios (HR) of depression with vitamin D deficiency using cut-off points of 50 nmol/l
and 37.5 nmol/l (see caption to Fig. 3 for explanation of symbols).
Hazard Ratio Hazard Ratio
Study or subgroup log (HR) s.e. Weight, % IV, random, 95% CI IV, random, 95% CI
Chan (2011)10 70.3014 0.17883 25.5 0.74 (0.52, 1.05)
May (2010)9 0.3514 0.02432 39.0 1.42 (1.35, 1.49)
Milaneschi (2010)35 0.5905 0.08063 35.5 1.80 (1.54, 2.11)
Total (95% CI) 100.0 1.31 (0.97, 1.77)
Heterogeneity: t2 = 0.06; w2 = 21.98, d.f. = 2 (P50.0001); I 2 = 91%
0.2 0.5 1 2 5
Test for overall effect: Z = 1.77 (P = 0.08)
Fig. 6 Cohort studies: forest plot of the hazard ratios (HR) of depression with vitamin D deficiency using cut-off points of 50 nmol/l
and 75 nmol/l (see caption to Fig. 3 for explanation of symbols).
Milaneschi et al were pooled with the HR of depression for vitamin No planned subgroup or sensitivity analysis could be
D below v. above 37.5 nmol/l from the study by May et al (Fig. 5). performed because of insufficiently reported data and inability
The overall HR in this analysis was not significant (HR = 1.04, 95% to obtain such data from authors.
CI 0.59–1.86). In the second analysis using cut-off points, the HR of
depression for vitamin D below v. above 75 nmol/l from the May et
al study was pooled with the other results (Fig. 6). This also gave a Discussion
non-significant HR of 1.31 (95% CI 0.97–1.77). Interestingly, using
the cut-off point of 75 nmol/l compared with 37.5 nmol/l changed Our systematic review identified one case–control study, ten cross-
the direction of the effect in this study. This appears to result from sectional studies and three cohort studies investigating the
the highest hazard rate, and largest number of participants, being association between depression and vitamin D deficiency, but
in the 37.5–75 nmol/l category. Therefore, if this group is included no randomised controlled trial. The single case–control study
in the vitamin D deficient group (cut-off point 75 nmol/l), the HR showed a moderate difference in vitamin D levels between women
suggests an increased risk of depression with vitamin D deficiency. with depression and healthy controls. Meta-analysis of the cross-
However, if this group is included in the normal vitamin D group sectional studies demonstrated an increased but non-significant
(cut-off point 37.5 nmol/l), the HR suggests a decreased risk of odds of depression for the lowest compared with the highest
depression with vitamin D deficiency. Therefore, the effect of vitamin D categories (OR = 1.31, 95% CI 1.00–1.71, P = 0.05).
vitamin D deficiency at levels below 50 nmol/l cannot be reliably Limiting the analysis to studies with an average participant age
determined from this study. of 65 years or over did not substantially change the overall
105Anglin et al
estimate or statistical significance. There was considerable overall quality of the evidence from each study is low and
variability in the vitamin D categories used in the cohort studies, therefore some uncertainty remains about the true association
and therefore three different meta-analyses were performed. Our between vitamin D deficiency and depression.
pooled HR of the lowest compared with the highest vitamin D
categories in the three cohort studies showed a significantly Implications of the study
increased HR of depression with low vitamin D levels The importance of vitamin D to many brain processes including
(HR = 2.21, 95% CI 1.40–3.49, P50.001). The pooled change in neuroimmunomodulation and neuroplasticity suggests that it
ln(HR) of depression per 20 nmol/l change in vitamin D level might have a role in psychiatric illness such as depression. The
across the three cohort studies also showed an increased hazard biological plausibility of the association between vitamin D and
of depression with decreasing vitamin D concentration, although depressive illness has been strengthened by the identification of
this was not significant (b70.19, 95% CI 70.41 to 0.04, P = 0.1). vitamin D receptors in areas of the brain implicated in
Finally, we analysed the data using different cut-off points as depression,4 the detection of vitamin D response elements in the
provided in the studies, which yielded different but non-significant promoter regions of serotonin genes,60 and demonstration of
pooled HR: 1.04 (95% CI 0.59–1.86) v. 1.31 (95% CI 0.97–1.77). interactions between vitamin D receptors and glucocorticoid
Overall, the summary estimates of all analyses suggest a relationship receptors in the hippocampus.61 Given the high prevalence of both
between vitamin D and depression, and all but one were close to vitamin D deficiency and depression, an association between these
being statistically significant. two conditions would have significant public health implications,
particularly as supplementation with vitamin D is cost-effective
Strengths and limitations and without significant adverse effects. The observational studies
To the best of our knowledge this is the first systematic review or to date provide some evidence for a relationship between vitamin
meta-analysis that has analysed the relationship between vitamin D deficiency and depression, but RCTs are urgently needed to
D deficiency and depression. We performed a transparent and determine whether vitamin D can prevent and treat depression.
methodologically rigorous systematic review of the literature.
Rebecca E. S. Anglin, MD, PhD, FRCPC, Department of Psychiatry and Behavioural
We developed a comprehensive search to identify articles and Neurosciences and Medicine, McMaster University; Zainab Samaan, MRCPsych,
assessed their eligibility, extracted data and assessed risk of bias PhD, Department of Psychiatry and Behavioural Neurosciences, McMaster University;
Stephen D. Walter, PhD, Department of Clinical Epidemiology and Biostatistics,
in each study in duplicate with a good level of agreement. Our McMaster University; Sarah D. McDonald, MD, MSc, Division of Maternal-Fetal
protocol was developed a priori and any post hoc analyses were Medicine, Departments of Obstetrics and Gynecology, Diagnostic Imaging and Clinical
clearly identified. A particular strength was the method used Epidemiology and Biostatistics, McMaster University, Hamilton, Ontario, Canada
and extensive analyses performed in an attempt to present the data Correspondence: Dr Rebecca Anglin, Department of Psychiatry and
in a uniform and consistent manner to allow for comparison and Behavioural Neurosciences, F413-1 Fontbonne Building, St Joseph’s Hospital,
50 Charlton Avenue E, Hamilton, Ontario L8N 2A6, Canada. Email:
combination. We were also successful in obtaining supplemental anglinr@mcmaster.ca
information from several authors, which allowed us to include
First received 24 Nov 2011, final revision 11 July 2012, accepted 20 Aug 2012
the majority of studies.
There are several limitations to our systematic review. As, at
the time of our review, there was no RCT of vitamin D for Funding
depression our review was restricted to observational studies,
There was no dedicated funding to support this study. R.A. is supported by an Ontario
which usually yield lower-quality evidence than RCTs. Reverse Mental Health Foundation Research Training Fellowship Award, Z.S. is supported by
causality, in which patients with depression have less exposure Hamilton Health Sciences New Investigator Fund and S.M. is supported by a Canadian In-
stitutes of Health Research New Investigator Award.
to the sun and therefore lower vitamin D levels, cannot be ruled
out in the cross-sectional studies. In addition there were potential Acknowledgements
biases across all study designs. Several cross-sectional studies had
unrepresentative samples, used self-reports of depression and had We thank Neera Bhatnager, librarian, McMaster University Health Sciences Library, for her
assistance in developing the search strategy and Peter Szatmari for his critical review of
small sample sizes. The study results were generally consistent, the manuscript.
with the exception of those from Pan et al who reported a
decreased odds of depression with low vitamin D.11 This was the References
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107British Journal of Psychiatry doi: 10.1192/bjp.bp.111.106666 Vitamin D deficiency and depression in adults: systematic review and meta-analysis Rebecca E. S. Anglin, Zainab Samaan, Stephen D. Walter and Sarah D. McDonald Supplement DS1 Search strategy EMBASE Search Strategy 1 exp DEPRESSION/ 2 exp major depression/ 3 exp mood disorder/ 4 exp MOOD/ 5 exp AFFECT/ 6 (depression or depressive disorder* or mood disorder* or mental disorder* or affect or affective symptom* or affective disorder* or major depress* or unipolar depress* or psychiatric symptom* or mood).mp 7 1 or 2 or 3 or 4 or 5 or 6 8 exp vitamin D/ 9 exp vitamin D deficiency/ 10 exp vitamin blood level/ 11 exp cholecalciferol/ 12 exp ergocalciferol/ 13 (vitamin D or vitamin D deficien* or hydroxycholecalciferol* or 25-hydroxyvitamin D or cholecalciferol* or ergocalciferol* or calcifediol* or calcitriol* or hydroxyvitamin*).mp 14 8 or 9 or 10 or 11 or 12 or 13 15 7 and 14 16 Nonhuman/ not human/ 17 15 not 16 MEDLINE and Pubmed Search Strategy 1 exp Depression/ 2 exp Mood Disorders/ 3 exp Depressive Disorder/ 4 exp Affect/ 5 exp Affective Symptoms/ 6 (depression or depressive disorder* or mood disorder* or mental disorder* or affect or affective symptom* or affective disorder* or major depress* or unipolar depress* or psychiatric symptom* or mood).mp 7 1 or 2 or 3 or 4 or 5 or 6 8 exp Vitamin D/ 9 exp Vitamin D Deficiency/ 10 exp cholecalciferol/ 11 exp ergocalciferol/ 12 exp Hydroxycholecalciferols/ 13 (vitamin D or vitamin D deficien* or hydroxycholecalciferol* or 25-hydroxyvitamin D or cholecalciferol* or ergocalciferol* or calcifediol* or calcitriol* or hydroxyvitamin*).mp 14 8 or 9 or 10 or 11 or 12 or 13 15 7 and 14 16 Animals/ not humans/ 17 15 not 16
PsycINFO Search Strategy 1 exp Major Depression/ 2 exp Psychiatric Symptoms/ 3 exp Emotional States/ 4 exp Mental Disorders/ 5 exp Affective Disorders/ 6 (depression or depressive disorder* or mood disorder* or mental disorder* or affect or affective symptom* or affective disorder* or major depress* or unipolar depress* or psychiatric symptom* or mood).mp 7 1 or 2 or 3 or 4 or 5 or 6 8 exp Vitamins/ 9 exp Vitamin Deficiency Disorders/ 10 (vitamin D or vitamin D deficien* or hydroxycholecalciferol* or 25-hydroxyvitamin D or cholecalciferol* or ergocalciferol* or calcifediol* or calcitriol* or hydroxyvitamin*).mp 11 8 or 9 or 10 13 7 and 11 AMED Search Strategy 1 exp Depression/ 2 exp Depressive Disorder/ 3 exp Affective disorders/ 4 (depression or depressive disorder* or mood disorder* or mental disorder* or affect or affective symptom* or affective disorder* or major depress* or unipolar depress* or psychiatric symptom* or mood).mp 5 1 or 2 or 3 or 4 6 exp Vitamin D/ 7 exp cholecalciferol/ 8 exp Vitamins/ 9 exp Dietary supplements/ 10 (vitamin D or vitamin D deficien* or hydroxycholecalciferol* or 25-hydroxyvitamin D or cholecalciferol* or ergocalciferol* or calcifediol* or calcitriol* or hydroxyvitamin*).mp 11 6 or 7 or 8 or 9 or 10 12 5 and 11 CINAHL Search Strategy S1 Depression + S2 Affective Disorders + S3 Mental Disorders + OR Mental Disorders, Chronic S4 depression or depressive disorder* or mood disorder* or mental disorder* or affect or affective symptom* or affective disorder* or major depress* or unipolar depress* or psychiatric symptom* or mood S5 Vitamin D + OR Vitamin D Deficiency + OR Cholecalciferol OR Ergocalciferols S6 vitamin D or vitamin D deficien* or hydroxycholecalciferol* or 25-hydroxyvitamin D or cholecalciferol* or ergocalciferol* or calcifediol* or calcitriol* or hydroxyvitamin* S7 S1 or S2 or S3 or S4 S8 S5 or S6 S9 S7 and S8
Supplement DS2 Detailed eligibility criteria The following study designs were eligible for inclusion: (1) (RCTs) that enrolled adults (age ≥ 18) with depression (major depressive disorder, depressive episode or depression NOS) and reported depression as the outcome of interest as defined below or depressive symptoms measured using a validated scale. (2) RCTs that enrolled any adults and reported depression outcomes of interest. (3) case- control studies that compared adults with depression to healthy controls and reported vitamin D measurements. (4) cross-sectional studies that measured vitamin D levels in adults and reported depression outcomes of interest associated with vitamin D deficiency (as defined by each study, Tables 1 & 2) compared to those with normal vitamin D. (5) cohort studies that measured serum vitamin D levels in adults and reported the rates of depression as the outcome of interest at follow-up for those with vitamin D deficiency compared to those with normal vitamin D.
Supplement DS3 Modified Newcastle–Ottawa Scales
Newcastle-Ottawa Scale for case–control studies data abstraction form26
Bias Case control * High Quality
Selection Is the case definition Yes, with independent validation Yes, eg record linkage or based No description
adequate? on self report
(max 4*)
Representativeness of the Consecutive or obviously Potential for selection bias or
cases representative series of cases not stated
Selection of controls Community controls Hospital controls No description
Definition of controls No history of disease (endpoint) No description of source
Comparability Cases and controls on the Study controls for important factor No control for any important
basis of the design or (chronic diseases, BMI or physical factor
(max 2*) analysis activity)
Study controls for a 2nd important No control for a 2nd important
factor factor
Exposure Ascertainment of exposure Secure record Interview not blinded to Written self report No des’n
Structured interview where blind case/control status or medical record
(max 3*) to case/control status only
same method of Yes No
ascertainment for cases
Non-response rate Same rate for both groups Non respondents described Rate different and
no designationNewcastle–Ottawa Scale for cohort studies data abstraction form26
Bias Cohort * High Quality
Selection Representativeness of exposed cohort Truly representative of the general Selected group eg: No description of
(Vitamin D deficient and insufficient population particular disease derivation of cohort
(max 4*) participants) Somewhat representative of general group, particular
population occupation
Selection of non exposed cohort Drawn from the same community as the Drawn from a different no description of
(adequate vitamin D levels) exposed cohort source derivation of non
exposed cohort
Ascertainment of exposure Reliable measurement of vitamin D Reported intake of no description
vitamin D
Demonstration that outcome of interest yes no
was not present at start of study
Comparability Comparability of cohorts on basis of Study controls for important factor (chronic Fails to control for an
design or analysis diseases, BMI or physical activity) important factor
(max 2*)
Study controls for any additional factor Does not control for
any factors
Outcome Assessment of outcome Independent blind assessment Self report No description
Record linkage
(max 3*) Was follow-up long enough for outcome Yes (>=3 months) No (80% No statement
and no description of
Subjects lost to follow up unlikely to the lost
introduce bias – small # lost (Newcastle–Ottawa Scale adapted for cross-sectional studies data abstraction form26
Bias Cross-Sectional Study * High Quality
Selection Representativeness of exposed cohort Truly representative of the general Selected group eg: No description of
(Vitamin D deficient participants) population particular disease derivation of
(max 3*) Somewhat representative of general group, particular cohort
population occupation
Selection of non exposed cohort Drawn from the same community as the Drawn from a no description of
(adequate vitamin D levels) exposed cohort different source derivation of non
exposed cohort
Ascertainment of exposure (Vitamin D Secure record (reliable measurement of Reported intake of no description
measurement) vitamin D) vitamin D
Demonstration that outcome of interest N/A
was not present at start of study
Comparability Comparability of cohorts on basis of Study controls for chronic diseases or No control for any
design or analysis other important factor important factors
(max 2*) Study controls for any additional factor
Outcome Assessment of outcome (depression) Independent blind assessment Self report No description
Record linkage
(max 1*) Was follow-up long enough for N/A
outcome to occur
Adequacy of follow up of cohorts N/ASupplement DS4 Adjustment for potential confounding variables for analyses across included studies
CASE-CONTROL STUDIES
Study, Year Adjusted variables
Eskandari, 2007 None
CROSS-SECTIONAL STUDIES
Study, Year Adjusted variables
Ganji, 2010 Age, sex, race/ethnicity, geographical location, urbanization, vitamin/mineral supplement use, prescription medication
use, poverty income ratio, BMI, serum creatinine
Hoogendijk, 2008 Age, sex, BMI, smoking, chronic conditions
Johnson, 2008 No OR provided, study adjusted for demographic characteristics, sunlight exposure, supplemental intake of vitamin D,
milk intake
Lee, 2010 Age, center, smoking, physical activity, alcohol, BMI, life events, psychotropic drugs and morbidities
Nanri, 2009 Age, sex, BMI, job position, marital status, alcohol, folate intake
Pan, 2009 Age, sex, urban/rural, BMI, physical activity, smoking status, number of chronic diseases, social activity level, marital
status, household income, geographical location
Stewart, 2010 Age, sex, social class, season, vitamin D supplementation, smoking, BMI, long-standing illness, subjective general
health
Wilkins, 2006 Age, ethnicity, sex, season
Wilkins, 2009 Unadjusted OR calculated, study adjusted for SBT score, PPT score, BMD, age, race
Zhao, 2010 Age, sex, ethnicity, education, marital status, BMI, serum creatinine, physical activity, alcohol, number of chronic
diseases
COHORT STUDIES
Study, Year Adjusted variables
Chan, 2011 Age, BMI, education, PASE, number of ADLs, DQI, smoking status, alcohol use, season of measurement, number of
chronic diseases, CSI-D score and serum (ln) PTH concentration
May, 2010 Age, sex, diabetes, season, PTH, hypertension, coronary artery disease, prior MI, heart failure, prior fracture, renal
failure
Milaneschi, 2010 Age, baseline CES-D, ADL disabilities, use of antidepressants, number of chronic diseases, SPPB, high PTH, season
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